Hepatically metabolised (hydroxylation and N-de-alkylation)This is slower, therefore there is a greater risk of systemic toxicity.

Stable in solution

Esters

Heat-sensitiveCannot be autoclaved.

Rapidly hydrolysed in plasmaOrgan independent elimination.

Have a greater incidence of allergyDue to the inactive metabolite PABA.

Amine group length

Potency and toxicity increase as carbon-chain increases

Toxicity (but not potency) continues to increase beyond 10 carbons

IsomerismAlters behaviour:

Levobupivacaine is less toxic

R-ropivacaine is less potent and more toxic

Key Characteristics of Local Anaethetics

Characteristics are related to chemical structure. These include:

Potency

Potency is expressed with the minimum effective concentration of local anaesthetic (Cm)This is the concentration of LA that results in complete block of a nerve fibre in 50% of subjects in standard conditions. More potent agents have a lower Cm.

Vasodilator propertiesIn general, local anaesthetics cause vasodilation in low concentrations, and vasoconstriction at high concentrations (except cocaine, which causes vasoconstriction at all concentrations).

Toxicity

Toxicity occurs when there is an excess plasma concentrationThis occurs when the rate of drug entering the systemic circulation is greater than the drug leaving the systemic circulation due to redistribution and metabolism.

Toxicity is related to the:

Drug factors

Drug usedAgents are compared using the CC/CNS ratio, which is the ratio of the dose of drug required to cause cardiovascular collapse (CC) compared to the dose required to cause seizure. It is a crude alternative to the therapeutic index.

Dose usedContinuous infusions are more likely to cause a delayed onset of local anaesthetic toxicity.

Block factors

Site of administrationThis affects the rate of uptake into the systemic circulation, and the likelihood of inadvertent intravascular injection. Ranked (from highest to lowest):

Intravascular (obviously)This is the most common cause of LA toxicity.

Site is also relevant here: an injection into the carotid artery will cause toxicity at a lower dose than if injected into a peripheral vein.

Hepatic diseaseReduces clearance of amides, which may cause toxicity with repeated doses or use of infusions.

AgeOrgan blood flow (and therefore clearance), as well as pharmacokinetic interactions may affect clearance of LA. Both children and the elderly have reduced clearance of LA.

AcidosisIncreases unionised portion.

HypercarbiaIncreases cerebral blood flow.

Cardiac Toxicity

Cardiac toxicity occurs due to:

Blocking of the cardiac Na+ channel (K+ and Ca2+ channels may also be involved)Severity of toxicity will vary depending on how long the agent binds to the channel, with less toxicity caused by agents spending less time bound:

LignocaineSpends the shortest time bound to the channel, so causes the least amount of toxicity. This is also why lignocaine can be used as an antiarrhythmic, but other agents can not.

BuipivacaineTakes 10x as long to dissociate as lignocaine. This can lead to re-entrant arrhythmias, and then VF. The risk of this is increased in tachycardia due to use-dependent blockade.

RopivacaineDissociates more rapidly from cardiac channels than bupivacaine.